1. Dent Clin N Am 52 (2008) 129153Management of Oral Infections in Cancer PatientsMark A. Lerman, DMDa,b, Joel Laudenbach, DMDc,Francisco M. Marty, MDb,d,e, Lindsey R. Baden, MDb,d,e, Nathaniel S. Treister, DMD, DMSca,b,e,*a Division of Oral Medicine and Dentistry, Brigham and Womens Hospital,75 Francis Street, Boston, MA 02115, USA b Harvard School of Dental Medicine, 25 Shattuck Street, Boston, MA 02115, USA cDepartment of Oral Medicine and Diagnostic Sciences, University of Illinois at Chicago School of Dentistry, 801 S. Paulina Street, Chicago, IL 60612, USA dDivision of Infectious Diseases, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA eDana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA Patients who have cancer are at risk both for newly acquired infectionsand, more often, from exacerbation of chronic infections or reactivationof latent viruses. During cancer therapy, the neutrophil count may below, placing patients at risk for bacterial infections (in particular, odonto-genic infections) [1,2]. Compromised lymphocyte function places them atrisk for infections in which immunity is mediated by T-cells, especially fun-gal and viral infections. The presence of chemotherapy-induced mucositismay act as a portal of entry for oral bacteria into the blood stream, leadingto bacteremia and sepsis. It is during this period that oral infections havea high morbidity and even mortality rate for patients. After cancer therapy, and for the rest of their lives, patients may continue toexperience some degree of immune compromise and suboptimal lymphocytefunction; therefore, the oral health care specialist should have a high indexof suspicion for oral lesions that do not heal, as they may be infectious inetiology. Furthermore, an atypical presentation of an oral infection may bethe rst sign of compromised immune function from an occult primary cancer,or it may represent evidence of relapse of a treated cancer.* Corresponding author. Division of Oral Medicine and Dentistry, Brigham and WomensHospital, 1620 Tremont Street, Suite BC-3-028, Boston, MA 02120.E-mail address: ntreister@partners.org (N.S. Treister).0011-8532/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.cden.2007.10.006 dental.theclinics.com

2. 130 LERMAN et alHistory and examination The history must include the cancer diagnosis and status; the nature,duration, and dates of previous and ongoing anti-neoplastic treatments;past medical history; current medications; drug allergies; prior history oforal and non-oral infections; and history of the present illness, includingsymptoms, onset, duration, any tests already ordered, and treatments ren-dered. A thorough past dental history, including recent visits; treatmentfor pulpal disease, including endodontic therapy; and a history of pericoro-nitis, recent extractions, and treatment for periodontal disease help to deter-mine a patients risk for bacterial infection. The patient should be evaluated for fever, and the area in question mustbe carefully examined and pulp testing done as necessary. Dental radio-graphs must be taken if an odontogenic source is suspected. Other imagingmodalities such as CT and MRI may be required to evaluate the extent ofthe lesion. Serology, cultures, smears, and especially biopsy are often neces-sary to identify the process and suspected pathogen.Bacterial infectionsOdontogenic infections Odontogenic infections, either of pulpal or periodontal origin, are fre-quently encountered in cancer patients. Any patient who has spontaneousor provoked dental pain, swelling, or evidence of purulent discharge mustbe considered to have an odontogenic infection until proven otherwise. Asthe inammatory response may be muted due to myelosuppression, the clin-ical signs of erythema, swelling, and purulence are highly variable, and theabsence of these features is insucient to rule out infection.Infections related to caries and nonvital teeth In the presence of dental pain, large restorations, prior endodontic ther-apy, gross clinical caries, radiographic evidence of restorations or caries nearthe pulp, periapical radiolucencies, trismus, and dysphagia should allheighten the suspicion of an odontogenic infection [3,4]. It is not uncommonfor a previously asymptomatic endodontically treated tooth with a radio-graphically adequate apical seal to become symptomatic during severe neu-tropenia (Fig. 1). This is most likely explained by an acute exacerbation ofa subclinical chronic periapical infection, rather than true acute failure ofendodontic therapy. Periapical infections arising from posterior maxillary teeth may perforatethe Schneidarian membrane and cause a sinusitis characterized by pain,headaches, and maxillary tenderness. Imaging with intraoral radiographsand maxillary sinus CT are required for diagnosis. Treatment includes elim-inating the source of infection as well as at least 3 to 4 weeks of 3. ORAL INFECTIONS IN CANCER PATIENTS131Fig. 1. Failing endodontic therapy in a patient who has advanced acute myelogenous leukemia.(A) Ulceration and necrosis of the palatal gingiva adjacent to tooth #13 that was negative forherpes simplex virus (HSV) on culture; (B) periapical radiograph demonstrating adequate api-cal ll with small periapical radiolucency. The tooth was treated many years previously and didnot demonstrate any evidence of failure until very late in disease.antimicrobial therapy directed at both oral ora and sinus pathogens [5].When multiple adjacent maxillary teeth present with pain, a primary bacte-rial or fungal acute sinusitis should be suspected. Empiric therapy with clindamycin or amoxicillin/clavaunate should beinitiated for periapic infections owing to potential penicillin resistance [4].Incision and drainage may be appropriate in the presence of a uctuantswelling, or extractions may be indicated, rst ensuring that there are ade-quate platelets [6]. Although 50,000 platelets/mL is ideal, patients whohave lower platelet levels may undergo tooth extraction if rigorous localmethods to control bleeding are performed (see the article by Brennanand colleagues elsewhere in this issue). Patients may also require antibacte-rials and chlorhexidine oral rinses and should be followed up until the areasare healed. Progression of periapic infections that are untreated or unresponsive totreatment may lead to osteomyelitis of the jaws, resulting in swelling,pain, suppuration, sinus tract formation, bone sequestration, and a radio-graphically characteristic moth-eaten appearance [7]. Oro-cutaneousstulae may form. Patients who have metastatic bone disease treated withhigh-potency intravenous bisphosphonate therapy may develop a secondaryosteomyelitis within areas of bisphosphonate-associated osteonecrosis of thejaw [8] (see the article by Ruggerio and Woo elsewhere in this issue). Treatment typically requires long-term broad-spectrum antibiotic ther-apy in both situations as the infections often contain polymicrobial oralora; adequate surgical debridement and possibly hyperbaric oxygen ther-apy should be considered [8,9]. In rare cases, localized spread of infectioncan result in cavernous sinus thrombosis or Ludwig angina. Each requiresimmediate hospitalization and aggressive treatment with intravenous antibi-otic therapy and possible surgical management because of the high risk ofmortality [9]. 4. 132LERMAN et alPeriodontal infections and pericoronitis Chronic periodontal disease of varying severity is ubiquitous in the adultpopulation. Exacerbation of chronic periodontal disease may not exhibitthe traditional clinical signs of inammation and swelling in patients whohave severe neutropenia [10]. Although oral mucositis and neutropeniaare well-established risk factors for Viridans streptococci bacteremia, mar-ginal ulceration and infection of the periodontium also may lead to bacter-emia, and the severity of periodontal disease and inammation is alsothought to be related to the risk of bacteremia [1113]. Rarely, periodontalinfections may be one of the initial presenting signs of underlying malig-nancy (Fig. 2). The evaluation should include examination for supra- and subgingivalplaque and calculus, percussion, assessment of mobility, periodontal prob-ing, and radiographic evaluation for bone loss and periodontal abscessformation [14]. The course of periodontal destruction in chronically myelo-suppressed individuals resembles what is often seen in patients who havepoorly controlled diabetes mellitus in terms of both aggressive behaviorand unpredictable response to conventional therapies, sometimes necessitat-ing extraction of the involved teeth [15]. Pericoronitis associated withFig. 2. Peri-implant abscess formation in a patient who was recently diagnosed with acute lym-phocytic leukemia. Patient was diagnosed 2 weeks following implant placement for missingtooth #13. (A) Abscess and purulent discharge at the gingival margin; (B) periapical radiographdemonstrating excellent osteointegration without evidence of infection/failure; (C) complete res-olution of lesion following 3 days of clindamycin therapy. 5. ORAL INFECTIONS IN CANCER PATIENTS 133partially erupted third molars often features ulceration and necrosis, whichmay represent an additional pathway for bacteremia (Fig. 3) [16]. Opercu-lum removal or extraction may be indicated in severe cases or when pro-found extended neutropenia is anticipated (eg, allogeneic stem celltransplantation). Necrotizing ulcerative gingivitis and periodontitis presentas painful ulcerations of the gingiva, sometimes with exposure of bone usu-ally arising in areas of pre-existing periodontal infection; it may spread tothe nonkeratinized tissues (Fig. 4) [12]. Treatment of acute exacerbation of periodontal disease includes scalingand curettage, extraction of hopeless teeth, and topical and systemic antimi-crobial therapy, usually with agents that target oral anaerobic bacteria suchas penicillin, clindamycin, or metronidazole.Parotitis Acute parotitis is an uncommon infectious complication of the parotidglands, characterized by a unilateral painful, indurated, erythematous swell-ing of the aected side of the face [17]. This is usually caused by an ascend-ing bacterial sialadenitis (most commonly Staphylococcus aureus), andsuppuration may be noted from the duct orice. The principal risk factorsin cancer patients are myelosuppression and decreased salivary ow, eitherdue to chemotherapy, radiation, and/or dehydration. An MRI or a CT scanmay be helpful in ruling out a neoplastic process or identifying a sialolith,respectively. The empiric antibiotic of choice is amoxicillin/clavaunate or clindamycintherapy, but any purulent material should be sent for culture and antimicro-bial susceptibility testing. Warm compresses to the site, adequate rehydra-tion, and nutritional support are important adjunctive measures.Although exceedingly rare, infections such as tuberculous parotitis shouldbe considered when there is parotid gland enlargement in chronically immu-nosuppressed patients [18].Fig. 3. Painful, necrotic pericoronitis in a patient who was recently diagnosed with acutemyelogenous leukemia. There is extensive leukemic inltration of the gingiva. 6. 134 LERMAN et alFig. 4. (A, B) Ulceration and necrosis of the anterior mandibular gingiva in areas of advancedperiodontal disease and loss of attachment in a patient who has advanced chronic lymphocyticleukemia.Bacteremia Gram-positive cocci, including Streptococcus viridans, have increasinglyemerged as important agents of bacteremia in neutropenic patients [13].The presence of oral mucositis likely increases this risk as the mucosal bar-rier is breached; in patients being treated with hematopoietic cell transplan-tation (HCT), the severity of oral mucositis was found to be an independentpredictor of anaerobic bacteremia [19]. Cytopenic fevers are the most com-mon clinical characteristic of bacteremia and may persist despite negativeblood cultures [13,20,21]. S mitis septicemia has been associated with a toxicshock-like syndrome characterized by hypotension, rash, palmar desquama-tion, and acute respiratory distress syndrome [13,2224]. Because of poten-tial penicillin and cephalosporin resistance, vancomycin is used empiricallyto manage gram-positive cocci bacteremia in neutropenic cancer patientsuntil the organism is identied and susceptibilities known [2,13,20,21,25]. Oral prophylactic antimicrobial therapy is considered in some centers incancer patients during neutropenia, as some reports suggest this maydecrease the incidence of bacteremia; however, the potential toxicity andemergence of resistant organisms must be carefully considered [26,27]. Pro-phylaxis with quinolones is often used in this setting owing to their broad-spectrum activity, lack of myelosuppression, and good tolerability [28,29].Other ways to reduce bacteremia include use of granulocyte-colony-stimu-lating factor to reduce the period of profound neutropenia and measuresto reduce oral mucositis such as palifermin [2,23,30].Fungal infections Oropharyngeal candidiasis (OPC) is the most common fungal infection incancer patients, and Candida albicans, a commensal organism found in 34%to 68% of the normal healthy population, is the most common causativeagent [3134]. The incidence of OPC in cancer patients is variable and is 7. ORAL INFECTIONS IN CANCER PATIENTS 135inuenced by the underlying disease, immune status, intensity of anti-neoplastic treatment, and salivary gland function [35]. For example, beforetreatment, 50% of head and neck cancer patients have oral Candida coloni-zation; however, this increases to nearly 70% during active radiotherapy[36]. In the United States, the estimated incidence of disseminated candidi-asis is 60,000 to 70,000 cases per year and is associated with health care costsof $2 to 4 billion per year [37]. Deep fungal infections must be considered in patients who have nonheal-ing ulcerated lesions [3840]. Both environmental opportunistic molds, suchas Aspergillus and Zygomyces, and endemic fungi, such as Histoplasma cap-sulatum, should be considered. It is important to carefully assess exposuressuch as hobbies and social activities (eg, gardening, spelunking, and use ofmarijuana) and places of previous residence to properly assess potentialexposures. When deep fungal infections are suspected, clinically early path-ogen-specic antigen testing (eg, histoplasma antigen and A galactomannanantibody) and biopsy are essential for diagnosis. Imaging studies, includingCT and/or MRI, may be indicated to rule out deeper processes such assinus, osseous, and fascial/soft-tissue involvement and to evaluate fordisseminated disease [41].Clinical presentation Pseudomembranous candidiasis (thrush), erythematous candidiasis,hyperplastic candidiasis, and angular cheilitis are all forms of OPC, whosesymptoms may include generalized discomfort, dysgeusia, xerostomia, andburning. Pseudomembranous candidiasis is the most common form andpresents as symptomatic or asymptomatic white papules or plaques thatcan be wiped away with gauze, typically revealing a raw and erythematousbase (Fig. 5). More commonly encountered in patients who have profoundsalivary gland hypofunction, erythematous candidiasis presents as anFig. 5. Pseudomembranous candidiasis of the palate demonstrating multiple areas of Candidacolonization. 8. 136LERMAN et alatrophic red lesion that is often associated with burning symptoms. Thetongue and palate are typically aected, the former appearing smooth anddepapillated. Rarely, OPC presents as a distinct white plaque (hyperplasticcandidiasis) that cannot be rubbed away and may require biopsy to distin-guish this lesion from other white lesions. Although any oral mucosal sur-face may be involved, the palate, oropharynx, and tongue are mostcommonly aected. Patients who have angular cheilitis present with painful,dry, and cracked corners of the mouth that may easily bleed. This is fre-quently seen in combination with one of the intraoral forms of infection.Risk factors There are a number of factors that increase the cancer patients risk ofdeveloping OPC (Box 1). Salivary gland hypofunction is one of the most com-mon causes of recurrent OPC. Saliva possesses critical antimicrobial, fungi-static, and/or fungicidal protective elements that include histatins, secretoryIgA, secretory component, lysozyme, mucins, statherin, transferrin, lactofer-rin, and defensins [42,43]. These proteins and peptides inhibit adhesion andmultiplication of Candida on mucosal surfaces [42]. Saliva also containsphagocytes that help to regulate the growth of Candida. When saliva isreduced, there is a loss of these innate protective mechanisms, therefore settingthe stage for the development of OPC. Radiotherapy to the head and neck re-sults in irreversible salivary gland damage with a decrease in saliva productionafter as little as 20 Gy and increased viscosity [44]. Chemotherapy may causereversible salivary gland hypofunction [45]. Many patients are also takingmedications that have anticholinergic leading to salivary gland hypofunction.Antibiotics and corticosteroid use also increase the risk for candidiasis [46,47].DiagnosisDiagnosis can often be made by clinical inspection alone, by cytologicsmear, or in some cases may require speciation by culture. Classic pseudo-membranous candidiasis should be treated empirically and does notBox 1. Risk factors for Candida colonization in cancer patients Neutropenia (severity, duration) Use of broad-spectrum antibiotics Use of corticosteroids Salivary gland hypofunction Total body irradiation Colonization of multiple body sites Increased length of hospital stay Wearing of dentures 9. ORAL INFECTIONS IN CANCER PATIENTS 137typically require culture. However, in patients undergoing chemo- or radio-therapy, what appears to be erythematous candidiasis may well be the earlysigns of treatment-related mucosal toxicity [48,49]. When lesions are nonre-sponsive to therapeutic antifungal therapy, sensitivity studies should be con-sidered. Biopsy of persistent white, erythematous, or in particular, solitarynonhealing ulcerated lesions is indicated to rule out an underlying deep fun-gal infection.Topical management The Infectious Diseases Society of America (IDSA) has published guide-lines for the treatment of OPC in cancer patients [50]. Initial episodes ofOPC can be treated with clotrimazole (an azole) troches or nystatin (a poly-ene) oral suspension or pastilles for 7 to14 days (Table 1). Both compoundsbind to the fungal/yeast cell membrane and alter permeability, resulting inthe loss of essential intracellular elements [51]. Clotrimazole is a moderateinhibitor of cytochrome P450 3A4 and could result in elevated levels of sev-eral medications, including tacrolimus, cyclosporine, benzodiazepines, andHMG-Co A reductase inhibitors [51]. Clotrimazole and nystatin oral formu-lations contain dextrose and sucrose, respectively, and can increase a pa-tients risk for the development of dental caries as well as aect bloodglucose levels in diabetics. Amphotericin B (AmB) is another polyene anti-fungal agent that has been used infrequently in topical formulations (eg, loz-enges, suspensions) for the treatment of refractory OPC [35,46]. Oralappliances/dentures may act as fomites and should be disinfected by soakingin nystatin, chlorhexidine gluconate oral rinse, dilute sodium hypochlorite(1:10), or sodium benzoate 20 to 30 minutes daily. Appliances should alsobe left out of the mouth during sleep.Systemic management When systemic therapy is required, the ISDA guidelines recommend theuse of rst-generation triazoles (uconazole or itraconazole, 100200 mg/day) for 7 to 14 days for the treatment of OPC. Itraconazole inhibits fungalcell membrane formation and interferes with cytochrome P 450 activity.Table 1Topical therapies for oropharyngeal candidiasisClotrimazole troche (10 mg) 45 times qd 714 daysNystatin oral suspension (100,000 U/mL) 5 mL, 4 times qd 714 daysNystatin pastilles (200,000 U)45 times qd 714 daysFluconazole solution (10 mg, 3 tid)a or (100 mg, bid)b 714 daysAmB oral suspension (100 mg/mL) 1 mL, 4 times qd 714 days a Swish and spit protocol. b Swish and swallow protocol. 10. 138 LERMAN et alThere have been rare serious cardiovascular events associated with itracona-zole, and its use is contraindicated if a patient is taking cisapride, pimozide,and quinidine [51]. Voriconazole and posaconazole [52] are newer triazolesthat may be eective against uconazole- and itraconazole-resistant strainsof Candida and other non-albicans species [53,54], although success rates inthis setting are approximately 70% owing to cross-azole resistance. Echinocandins (caspofungin, micafungin, anidulafungin) and AmBformulations (AmB deoxycholate, lipid-based formulations) are systemicagents that may be used in refractory cases of clinically severe OPC. Theantifungal spectrum of caspofungin is relatively narrow and includesAspergillus and Candida spp [46,55], whereas AmB has a broader spectrumof activity. A recent Cochrane review of treatment interventions specicallyfor OPC in cancer patients concludes that there is weak and unreliableevidence to support which agents should be prescribed [35]. In the presentauthors experience, topical antifungal treatment is sucient for most casesof mild to moderate OPC. For patients who have symptomatic disease whosecurrent immune status makes them likely to relapse, uconazole is an eec-tive option for treatment and suppressive therapy until chemotherapy iscompleted or immunosuppression lowered. Use of intravenous agents, vor-iconazole, or posaconazole should be reserved for patients who have provenOPC that is drug resistant or for those who are intolerant to uconazole.Prevention In cancer and immunosuppressed patients, the goal of antifungal prophy-laxis is to avoid the increased morbidity/mortality associated with the devel-opment of OPC. The choice of prophylactic drug regimen depends on theunderlying malignancy, expected course of neutropenia, and/or expectedseverity/extent of oropharyngeal mucositis [56]. Drug toxicity, nancialcosts, and resistance are important considerations in the decision to imple-ment antifungal prophylaxis [57]. Chlorhexidine inhibits fungal cell adherence to denture materials and ep-ithelial cells [51,58] and may be used for prophylaxis. However, nystatin andchlorhexidine in combination may reduce the antifungal properties of bothmedications [49,59]. Prophylactic clotrimazole (10 mg, 5 times/day) has beenevaluated in the advanced HIV-infected population and was found to be lesseective than uconazole tablets in the prevention of Candida-associateddiseases [49,59,60]. In patients undergoing HCT, topical antifungals havenot been shown to reduce the incidence of invasive candidiasis [61]. The IDSA guidelines recommend uconazole prophylaxis for patientsundergoing HCT with anticipated prolonged neutropenia, mucosal damage,or who have recently received udarabine or 2-chlorodeoxyadenosine [56].Fluconazole should be the choice in patients who have uconazole-susceptibleCandida and in health centers where C albicans is the predominant etiologyof invasive fungal disease [56]. In this setting, uconazole (400 mg/day) is 11. ORAL INFECTIONS IN CANCER PATIENTS 139typically given during the neutropenic period (ANC !500 cells/mm3)[51,62]. This practice is controversial and should be guided by the incidenceof fungal infections in the high-risk population. At transplantation centerswhere the incidence of fungal infections during the neutropenic period islow, uconazole prophylaxis is not used. Alternatives to uconazole for an-tifungal prophylaxis in patients undergoing cancer therapy (ie, chemother-apy and/or radiotherapy) include medications such as caspofungin ormicafungin [36,63].Resistance Resistant strains of Candida spp, especially to uconazole, are a concernin patients who are immunosuppressed, have had previous OPC, and/or re-quire suppressive antifungal therapy [36]. In addition, various studies haveshown that the Candida spp often change throughout the course of and afterradiotherapy/chemotherapy from mostly albicans to non-albicans species[58]; There are also dierences in colonization based on whether or not a pa-tient is ambulatory or hospitalized, and the stage of his or her cancer [33].Non-albicans spp that have been identied in cancer patients include C glab-rata, C krusei, C tropicalis, and C dubliniensis [33]; they are often resistant toconventional antifungal agents. When compared with C albicans, C glabrataexhibits varying degrees of resistance to the antifungal activity of somesalivary proteins and to antifungal medications [64]. Ueta and colleagues[65] showed in vitro that anticancer medications and radiotherapy resultin increased Candida proliferation, adherence, and antifungal drug resis-tance. In breakthrough OPC, culture and sensitivity testing can help withchoosing an alternative antifungal drug. These tests can better elucidate ifthe infection is due to a resistant strain and/or to dierent species with vary-ing sensitivities. As the clinical and laboratory markers of Candidia coloni-zation/active infection improve with advances in diagnostic technology,there is hope that antifungal therapeutics can be tailored to a patientscolonization prole [66].Management of deep fungal infections Management of invasive mold infection requires a multi-tiered approachthat includes (1) minimizing immunosuppression (eg, deceasing corticoste-roid dose and facilitating neutrophil recovery); (2) assessing for and control-ling permissive viral infections (eg, cytomegalovirus infection); (3) adequatesurgical debridement, especially for the vasotrophic molds (eg, Zygomycesand Aspergillus); and (4) targeted antifungal therapy. Depending on theseverity of illness, degree of organ insuciency (eg, renal or hepatic dysfunc-tion), and the organism causing invasive disease, a polyene (eg, amphoteri-cin B product), an azole (eg, voriconazole or posaconazole), or anechinocandin (eg, caspofungin, micafungin, or anidulafungin) could beused [3840]. 12. 140LERMAN et alViral infections Viruses are dependent on their host for replication and survival. Virusesreplicate in infected cells, progeny are released, and additional cells becomeinfected. A critical defense mechanism against viral infections is cell-mediated immunity, mediated by T lymphocytes; therefore, patients whohave compromised immune systems become more susceptible to infectionand potentially fatal complications [61]. Although certain viral infections may be recognized on clinical signs,denitive diagnosis often requires laboratory investigation. Commondiagnostic techniques include isolation by viral culture, detection of virus-specic antigens and antibodies, and light microscopy. Viruses themselvesare not visible by light microscopy, but their damaging eect on cells or in-tracellular cytopathic changes may be seen in tissue biopsies or exfoliativecytology specimens and are often characteristic. Most antiviral agents are designed to inhibit replication of the viralgenome and are administered by mouth or intravenously; topical treatmentsare generally less eective and generally not used in cancer patients. Pro-phylactic antiviral therapy, usually used against the Herpes family of vi-ruses, may be administered to patients whose level of immunesuppression substantially increases the likelihood of viral reactivation. Be-cause infections in cancer patients may lead to serious complications, em-piric treatment is often instituted based on a clinical impression beforedenitive diagnosis.Herpes virusesThere are currently nine known members of the Herpes family, eight ofwhich are pathogenic in humans (Table 2). Seroprevalence for each virusis generally high, and infection is life-long in that patients harbor latent cop-ies of the virus even when asymptomatic.Herpes simplex virus HSV-1 has historically caused infections in the orofacial area and HSV-2infections have traditionally involved the genitalia; however, this anatomicdistinction has become less clear [67]. Approximately 60% to 90% of thepopulation has been exposed to HSV-1 by age 70 [68,69]. Only 1% of thoseexposed (typically through contact with saliva or active perioral lesions) willdevelop primary herpetic gingivostomatitis, characterized by fever, malaise,pharyngitis, and diuse ulcers and erythema throughout the oral mucosa[70]. HSV establishes latency in the trigeminal ganglion. Reactivation ofthe virus from sunlight, hormonal changes, trauma, stress, illness, or im-mune compromise results in either asymptomatic shedding or recrudescentlesions [71,72]. Approximately 20% to 40% of the immunocompetent pop-ulation experiences recrudescent HSV infections. Most often, these presenton the lower vermillion border following a prodrome of tingling, as herpes 13. ORAL INFECTIONS IN CANCER PATIENTS141Table 2The human herpes viruses and key oral manifestations of diseaseHerpesSeroprevalence Clinical disease(s) in the head andvirus Alternate name(%)neckHHV-1 Herpes simplex-180 Acute herpetic gingivostomatitis Recrudescent herpetic infectionsHHV-2 Herpes simplex-220 Acute herpetic gingivostomatitis Recrudescent herpetic infectionsHHV-3 Varicella-zoster virus95 Chicken pox ShinglesHHV-4 Epstein-Barr virus90 Infectious mononucleosis Nasopharyngeal carcinoma Oral hairy leukoplakia Burkitt lymphoma Posttransplant lymphoproliferative disorderHHV-5 Cytomegalovirus 70 Nonspecic ulcersHHV-6 99 childhood roseolaHHV-7 85 childhood roseolaHHV-8 Kaposi sarcoma-associated 230 Kaposi sarcoma herpes virusCastleman disease Lymphomalabialis [71,72]; however, intra-oral lesions aecting the keratinized mucosalsurfaces (ie, hard palate, gingiva, and tongue dorsum) are occasionally seen[73]. These lesions develop as small (generally no greater than 0.5 cm indiameter) vesicles that rupture quickly and leave shallow, tender ulcerationsthat without treatment heal in 1 to 2 weeks [74]. Recrudescent HSV lesions in immunocompromised patients are painful,but their appearance is often dierent from lesions in otherwise healthypatients [72,75]. Lesions may present on any mucosal surface, keratinizedor nonkeratinized; they may be larger (O0.5 cm), single, and may persistfor months without the initiation of antiviral therapy. The atypical presen-tation often delays diagnosis, as the lesions may be mistaken for mucositis,aphthous ulcers, and other forms of pathology (Fig. 6). In patients who havecancer, recrudescent HSV may lead to potentially life-threatening dissemi-nated disease, and antiviral prophylaxis has become the standard of carefor many cancer therapy protocols [75,76]. Acute painful oral ulcers in can-cer patients, regardless of clinical appearance, must be considered to be re-crudescent HSV until proven otherwise. Viral culture is performed by swabbing an active lesion and submitting inviral culture medium, kept on ice, to a virology laboratory as soon as pos-sible. This technique does not distinguish between asymptomatic viral reac-tivation and shedding in the saliva, and HSV actually causing ulcers.Exfoliative cytology, coupled with direct uorescent antibody testing, pro-vides a diagnosis within hours and is especially useful when an immediatediagnosis is critical [68,77]. Tissue biopsies are indicated for persistent 14. 142 LERMAN et alFig. 6. Atypical gingival lesions in a patient who has refractory acute myelogenous leukemia.(A) Painful edematous reddish/purple marginal gingiva with focal areas of ulceration; (B) im-munohistochemistry demonstrating HSV-12 positivity (dark nuclei), providing nal diagnosisof recrudescent HSV infection.lesions in spite of therapy, and in patients for whom a denitive diagnosisremains elusive. Resistance to antiviral medications ranges from 4.1% to7.1% in immunocompromised patients and breakthrough infections arecommon [78]. Treatment of immunocompromised patients who have recrudescent HSVlesions involves oral or, in severe cases, intravenous antiviral therapy andsupportive care (Box 2). Acyclovir, which inhibits viral thymidine kinase,is typically rst-line therapy. Given the low bioavailability of acyclovirand its increased dosing requirements, valacyclovir and famciclovir aremore widely used as alternatives and are now available in genericBox 2. Treatment and prophylaxis of recrudescent herpessimplex virus in immunocompromised patientsTreatmentOral ACV 400 mg 3 times/day for 10 days or longerOral valacyclovir 5001000 mg twice/day for 10 days or longer(famciclovir has been recommended as an alternative at500 mg 2 times/day for 10 days) In the setting of recurrent outbreaks, long-term antiviral suppression can be deployedProphylaxisOral ACV 400800 mg 3 times/dayOral valacyclovir 5001000 mg twice/dayOral famciclovir 5001000 mg twice/day 15. ORAL INFECTIONS IN CANCER PATIENTS 143formulations. Lesions should be monitored to ensure resolution, and persis-tent lesions should be reevaluated for the emergence of resistant virus or forsuperinfection with another infectious agent. If acyclovir-resistant HSV isdetected, therapeutic options include foscarnet or cidofovir. Approximately 70% to 80% of seropositive patients developed HSVreactivation after HCT before acyclovir prophylaxis [79]; in the setting ofproper prophylaxis, this has been reduced to approximately 20% to 30%and has been associated with a signicant reduction in HSV disease [8082]. HSV infection is less commonly seen in patients undergoing radiationtreatment for head and neck cancer, although concomitant chemotherapylikely increases the risk [83].Varicella-zoster virus Varicella-zoster virus (VZV) causes primary varicella (chickenpox) andthe recurrent infection, zoster (shingles). As vaccination against varicella be-came widespread in the 1990s, primary varicella infection in childhood isnow rare. Breakthrough infections have been reported in some vaccineeswithin a year of inoculationdlikely related to vaccine failure, or years later,possibly related to waning immunity [84]dand long-term eectiveness ofthe vaccine is 80% to 85%. Therefore, recent vaccination guidelines callfor a second immunization to be administered later in childhood [85,86]. Ten to 20% of the general population develop zoster, with single episodesbeing common. Predisposing factors for reactivation include increasing age,altered cell-mediated immunity, malignancies, radiation, and use of cyto-toxic drugs [87,88]. Reactivation begins 70% to 80% of the time with a pro-dromal pain; however, some will experience prodromal pain without thesubsequent development of clinical lesions (zoster sin herpete) [8789].Typically, though, the prodrome is followed in 1 to 4 days by the develop-ment of unilateral, clustered vesicles and/or ulcers involving the skin or oralmucosa along one nerve dermatome; lesions heal with or without scarring.Zoster infections involving the V2 and V3 branches are not common, ac-counting for approximately 2% of all cases [89]. Because the pain associatedwith intra-oral zoster may be mistaken for an odontogenic infection, a thor-ough history and clinical examination are essential for correct diagnosis andappropriate treatment. Post-herpetic neuralgia aects 6% to 18% of zosterpatients older than age 60 and is characterized by pain that persists longerthan 4 months after the initial onset of the rash [90]. Approximately 20% to 40% of allogeneic and autologous HCT patientsexperience VZV reactivation. Herpes zoster is a common complication ofallogeneic HCT, seen in nearly one third of patients [91]. In these pro-foundly immunosuppressed individuals, complications may be severe andmay include dissemination, bacterial superinfection, scarring, and death[92,93] (see the article by Woo and Abdelsayed elsewhere in this issue). Although diagnosis of both varicella and zoster can often be made from theclinical presentation alone, it should be conrmed by viral culture. Neither 16. 144 LERMAN et alcytology nor tissue biopsy dierentiates between HSV and VZV infections.Treatment of zoster requires substantially higher doses of acyclovir thanthat used for HSV (because VZV is intrinsically less sensitive to antiviraltherapy), and supportive care [88,94]. In an immunocompromised population,a 1- to 2-week course of acyclovir, valacyclovir, or famciclovir is eective intreating active lesions and in reducing the incidence of post-herpetic neuralgiaif administered within the rst few days of infection onset [87,95]. Manage-ment of post-herpetic neuralgia is often challenging, and frequently involvestricyclic antidepressants, opioids, gabapentin, pregabalin, and/or topicalagents (lidocaine, capsaicin) [96]. Studies have indicated that prophylaxiswith acyclovir is eective in preventing VZV reactivation after HCT [91].Epstein-Barr virusEpstein-Barr virus (EBV) has been associated with infectious mononucle-osis, nasopharyngeal carcinoma, oral hairy leukoplakia (OHL), and variouslymphoproliferative disorders. EBV is spread through saliva, and 90% ofNorth American adults are estimated to be seropositive. Initial infection isoften subclinical, and the virus remains latent mainly in B cells and less com-monly in epithelial cells [97,98].Symptoms of infectious mononucleosis include fever, malaise, pharyngi-tis, and tonsillitis [99,100]. Diagnosis can be conrmed by a positive hetero-phile antibody test or EBV-specic antibodies. Palliative treatment only isrecommended as this is a self-limiting condition and studies have demon-strated little clinically signicant benet from administration of antiviralmedications [101].There is a strong association between EBV and lymphoproliferative ma-lignancies, including Burkitt lymphoma, Hodgkin lymphoma, and B-celllymphomas among solid organ and stem cell transplant recipients. Amongpreviously EBV seronegative HCT recipients, there have been reports ofposttransplant lymphoproliferative disorders and EBV pneumonitis associ-ated with EBV-infected donor hematopoietic cells [102,103]. Posttransplantlymphoproliferative disorders often presents initially as andenopathy or anextranodal mass along the gastrointestinal tract; this includes the oralcavity where these disorders may masquerade as gingival hyperplasia[104,105].OHL is a benign manifestation of EBV that is seen almost exclusively inimmunocompromised patients. They present as vertical white striations orplaques, usually on the lateral/ventral tongue bilaterally. These lesions donot wipe away and are often co-infected with Candida. Although it isseen predominantly in patients who have HIV infection, OHL has been re-ported in profoundly myelosuppressed patients, such as those with acuteleukemias [106]. Cultures are not useful, and the diagnosis of OHL is usuallythrough a tissue biopsy. OHL is self-limited and requires no treatment,although it tends to resolve with anti-retroviral therapy in patients infectedwith HIV. 17. ORAL INFECTIONS IN CANCER PATIENTS145CytomegalovirusApproximately 50% of the population is seropositive for cytomegalovi-rus (CMV), although symptoms are generally evident only in infants and im-munocompromised patients [107]. After initial infection, the virus is believedto remain latent in salivary glands, endothelial cells, and leukocytes, and istypically only reactivated in the context of profound immunosuppresion (eg,solid organ and stem cell transplantation) [108].Manifestations of CMV disease in immunocompromised hosts mayinclude retinitis, pneumonitis, encephalitis, hepatitis, and gastroenteritis.Intra-oral lesions present as nonspecic painful ulcers, usually present forweeks or months, on any mucosal surface. They are often mistaken for,or co-infected with, other viral or fungal infections [109,110].Antigenemia, polymerase chain reaction, and hybrid capture assays areused in transplant recipients to screen for use of pre-emptive prophylactictherapy, to treat active disease, and to monitor response to antiviral therapy[111]. In the case of oral lesions, cultures are unreliable (owing to the virusbeing located in the deep mucosa) and diagnosis usually requires biopsy[112].Treatment of CMV infection depends on the extent of involvement andunderlying degree of immune suppression. Ganciclovir was the rst agentapproved for use in treating CMV, and has been used eectively as prophy-laxis against reactivation of CMV in seropositive patients underoing HCT[113]. Closely related to gangciclovir is valganciclovir, which exhibits im-proved bioavailability [114116]. Intravenous cidofovir and foscarnet useis limited by nephrotoxicity, but may be used in patients who fail to respondto ganciclovir [117,118].Other herpes viruses HHV-6 is a lymphotrophic virus with two known variants (A and B)and has been isolated in immunocompromised hosts, although its clinicalfeatures are poorly dened. Infection with HHV-6 typically occurs in in-fancy and is often asymptomatic, although it may cause infantile roseola;the virus is believed to persist in salivary glands and T cells. HHV-6 hasbeen shown to reactivate in 40% to 60% of patients undergoing HCT[119122]. Reactivation of this virus may be associated with nonspecicndings such as fever and rash. Encephalitis, which is associated withType B, is a less frequently encountered but potentially life-threateningcomplication [123,124]. Although palatoglossal ulcers may be a sign of pri-mary HHV6 infection, oral lesions have not typically been described [125].Diagnosis is conrmed by blood culture or serology, and treatment with fo-scarnet or ganciclovir is currently the preferred approach [126], althoughtheir clinical ecacy in modifying outcomes is not established. HHV-7 is similar in many ways to HHV-6, also giving rise to infantileroseola. Seroprevalence is estimated at 85% in adults, and like HHV-6, per-sists in salivary glands and T-cells. It often becomes reactivated in an 18. 146 LERMAN et alimmunocompromised host, but has no specic oral manifestations. In onestudy, HHV-7 was associated with severe graft-versus-host disease and sep-sis in patients after HCT [127]. HHV-8 is best known for its association with Kaposi sarcoma, which wasseen frequently in patients who had AIDS before the advent of highly activeantiretroviral therapy, but not in chronically immunosuppressed cancerpatients [128]. HHV-8 has also been linked to lymphoproliferative disorders,including Castleman disease and primary eusion lymphomas [129131].Kaposi sarcoma presents as reddish purple vascular-appearing lesions andrequires biopsy for diagnosis.Papillomaviruses Of the more than 70 known subtypes of human papillomaviruses (HPV),subtypes 16 and 18 have known oncogenic potential, whereas subtypes 6and 11 are commonly associated with genital and cutaneous warts andhave low oncogenic potential. The oncogenic potential of HPV-16 and -18and cervical cancer is the basis for the two HPV vaccines recently approvedby the US Food and Drug Administration that target HPV-6/11/16/18 inone and 16/18 in the other [132,133]. Recently, an association has beenestablished between HPV and oropharyngeal cancer as well [134]. HPV-related lesions are not infrequently seen in immunosuppressed patientssuch as post-HCT. HPV infection presents as pink, painless, papillarymasses resembling papillomas, with common sites being the gingiva, tongue,or labial mucosa (Fig. 7). HPV causes a distinct cytopathic change that is readily seen on tissue sec-tions. Typing can be performed to establish whether the HPV is of the high-risk type. Treatment is by excision, and recurrence is common in theimmunocompromised patient population. Although viral particles haveFig. 7. Recurrent condylomas of the anterior maxillary gingiva in an immunosuppressedpatient following HCT. (Courtesy of Sook-Bin Woo, DMD, Boston, MA). 19. ORAL INFECTIONS IN CANCER PATIENTS147been detected in the laser plume during laser removal of such lesions, theclinical signicance with respect to infection risk is unclear [135,136].Summary Advances in medical care now allow cancer patients to live longer; yet,with improvements in survival come greater numbers of potential complica-tions. 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